Glucosides and process of making the same



Patented June 20, 1944 UNITED STATES PATEN 'r OFFICE J GLIlCOSIDES AND PROCESS OF MAKING THE SAME Karl Micscher, Riehcn,

Fischer, Summit Switzerland, Werner N. J., and Jules Beer, Basel,

Switzerland, assignors to Ciba Pharmaceutical- Products, Incorporated, Summit, N. J.

No Drawing. Application March 25, 1941, Serial No. 385,196. In

Switzerland March 16, 1938 10 Claims. (Cl. 260-210) This invention relates to the manufacture of new sugar derivatives of non-steroids having the efiect of steroid hormones by treating such nonsteroids with an etherifying sugar derivative in the presence of a catalyst useful in furthering.

diethyldiphenylethane, dianols, hydroxy-compounds of the stilbene series such as 4:4'-dihydroxystilbene, a a'-dialkyl-, -dialkenyl-, -dialklnyl-, -alkyl-arylor -diaryl-4:4'-dioxystilbeue such as am dimethyl-4:4'- dihydroxystilbene, a:a'-diethyl-4:4'-dihydroxystilbene, a methyl- '-ethyl-4:4' dihydroxystilbene, on diisopropyl-4:4'-dihydroxystilbene, a:c'-diethinyl-4:4'-

dihydroxystilbene or :a'-diDheny1- 4! ihydroxystilbene, further u-mono-alkyl-, -alkenyl-, -alkinylor -aryl-4:4'-dihydroxysti1bene such as methyl-, ethyl-, ethenyl-, ethinyl-, allylor phenyl- 4:4'-dihydroxysti1benes. Further also hydroxy-compounds of the polyphenylethane series which are substituted in ozand/r ad-positlon by alkenyl, alkinyl or alkylidenes, such as ,for example 3:4-(4':4."-dihydroxy-diphenyl)- 2:4-hexadiene, 2:3 -(4':4"-dihydroxydiphenyl) 1:3-butadiene, atoz'- diethiny1-4':4"'-dihydroxydiphenylethane, azc'-diallyl-2':2"-dihydroxydiphenylethane, a-ethinyl 4' :4" dihydroxy dip'henylethane, ethylidene-4' :4":4"'-trihydroxytriphenylethane.

Etheriiying sugar derivatives include such sugar derivatives as are capable of etherifying compounds containing hydroxyl groups. Particular mention is made of the acyl compounds and the acyloxy-halogen compounds of the saccharides. such as for example acetyl glucose, pentacetyl glucose and acetobromo glucose. As saccharides there may be used for instance mono dior trisacchariiies, such as glucosides, galactosides, or galactose-glucosides. The process of the inven tion may be carried out by known methods in presence of a catalyst useful in furthering etherincation, such as are described for example in Richter-Anschiitz, Chemie der Kohlenstoifverbindungen, vol. 2, 1st half, page 359 (1935) This text-book describes for example the action of hydrochloric acid on alcoholic sugar solutions, the reaction of alcohols with 1:2-oxides of sugars phenols and sugar acetates by zinc chloride or Dara-toluene sulfonic acid. But other known zincchlorlde, silver carbonate, mercury salts such and the manufacture of phenolgl'ycosides from catalysts furthering the etheriflcation may also be used, for example silver oxide, silver carbon- 'ate, mercury salts such as mercury oxide, mercury acetate (cf. "Berichte, vol. 62, page 990 (1929)) and mercury succinate, emulsin and the vglucosidase of yeast.

The new compounds may contain one or more saccharide residues in the molecule and also hydroxyl groups which are still free or have been esterifled or etherlfied. The saccharide residue may also be present in the form of derivatives, for instance in the form of their acylates.

The new compounds are characterised by their better solubility in water and are useful in therapeutics.

The following examples illustrate the invention:

Example 1 1 part by weight of 4:4'-dihydroxy-a:fi-dieth-- ylstilbene, 3 parts of penta-acetylglucose and 0.1 part of para-toluenesulfonic acid and 10 parts of benzene are boiled for five hours. The solution is then taken up in benzene and Washed with dilute caustic soda lye and water and then dried over sodium sulfate. After evaporating the benzene finally in a vacuum there is obtained the octa-acetyl-bis-glucoside o! dihydroxydiethylstilbene in the form of colorless crystals. F. 227- 230. It may be recrystallised from methanol or ethanol.

The acetyl derivative may be saponified by heating a methanol solution thereof with 1 part of a solution of 1 partof sodium in parts of methanol for a short time. Water is then added, whereby 4:4'-bis-(p-glucoside) -:p diethylstilbene is precipitated in the form of a whitepow- I der. It may be recrystallised from butanol and melts with decomposition at about 245. The saponiflcation may also be efl'ected with other hydrolising agents, for example sodium hydroxide.

In analogous manner there may be obtained the polysaccharides of for instance -4:4'-bis-'(filactoside) or 4 z4'i-bis- (fl -gentiobiosido) -d-glucoside or the same parent material.

The said saccharides can equally well be obtained by way of other etherifyins Sugar derivatives, such as the corresponding acetohalogen sugars or acetyl sugars even in presence of other catalysts furthering etheriiication, for instance as mercury acetate, mercury oxide and mercury succinate. emulsin or the giucosidase of yeast.

Example 2 4A parts by weight of 4:4'-dihydroxy-a:B-diethyl-diphenylethane, 3.6 parts by weight of benzoic acid anhydride and 50 parts by volume of dry pyridine are boiled for 2 hours in a reflux apparatus. The pyridine is distilled in vacuo and the residue taken up in ether whereby the dibenzoate of the 4:4'-dihydroxy-a:p-diethyl-diphenylethane which is sparingly soluble in ether is separated nearly quantitatively. The dibenzoate is suction-filtered and washed with ether. The ether solution is washed first with dilute sulfuric acid, then with sodium carbonate solution and finally with water. After drying it is evaporated and the oily residue is taken up in aqueous methanol. After standing for some time the monobenzoate of the 4:4'-dihydroxy-a:p-diethyl-diphenylethane crystallises, which after recrystallisation from methanol melts at 123- 126 C.

5 parts of freshly precipitated and dried silver oxide are introduced while stirring into a solution consisting of 2.4 parts of 4-hydroxy-4'-benzoxy-e:fi-diethyl-diphenylethane and 7.2 parts of aceto-bromoglucose in 50 parts by volume of dry quinoline. After stirring for a long time the reaction product is taken up in 200 parts of chloroform. The chloroform solution is filtered through an aluminium oxide filter in order to remove the silver ox de and the silver bromide,

then washed with dilute sulfuric acid, dilute sodium carbonate solution and water and after drying evaporated in a vacuum. The monotetracetyl-B-glucoside of the 4-hydroxy-4'-benzoxyetfi diethyl diphenylethane after chromatogra hic purification and recrystallization, melts at 156 C.

1.9 parts 'of this compound are suspended in 60 parts of methanol and the solution is stirred a room temperature with a solution of 0.3 part of sodium in 30 parts of methanol. After some hours a clear solution is obtained which is exactly neutralised with dilute acetic acid and then evaporated to a small volume. By add ng water the mono-B-glucos de of the 4!4'-dihyd1'OXV-a2B-diethyl-diphenylethane, which melts at 203-204 C. when recrystallised from aqueous methanol, is obtained.

The same product can be obtained in analogous manner by way of the mono-acetate or mono-propionate of the 4:4'-dihydroxy-:,B-diethyl-diphenylethane instead of with the monobenzoate, the corresponding mono-tetracyl-B- glucoslde of the 4-hydroxy-4'-acyloxy-:B-diethyl-dinhenylethanes being thereby formed intermediate products. The glucose radical of course be esterifled also with other acids acetic acid, for example with pronionic acid; Instead of glucose there may he introduced the radicals of other monosaccharldes, like mannose, arabino'se etc. using an etherify derivative 01' them and a catalyst usetulin furthering etheflfication. I

Example 3 1 part by weight of 4:4'-dihydroxy-a:p-diethylstiboestrol is dissolved in 10 parts by volume of pyridine and, after mixing with 0.65 vpart by volume of propionic acid anhydrlde, the whole is left standing for about 16 hours at a temperature of about 15 C. The solution so prepared is thereafter highly concentrated in a vacuum and the residue is taken up in ether. The ether solution is washed successively with dilute hydrochloric acid, aqueous sodium carbonate solution and water, and is finally driedand evaporated. The residue is dissolved in a mixture of benzene and pentane (1:1) and this solution is caused to flow through an adsorption column prepared in known manner with aluminium oxide. By developing with abenzenepentane mixture (1:1) there is obtained the dipropionate of 4:4'-dihydroxy-a:B-diethyl-stilbene melting at 102-404 C., then by further developing with the aid of benzene alone, the monopropionate of 4:4'-dihydroxy-uzfi-diethyl-stilbene is isolated which after recrystallising'from ether-pentane forms needles melting at 92-94 C. By continuing the washin out of the adsorption column with ether unchanged starting material is finally obtained.

7.2 parts by weight of acetobromoglucose are caused to react with 2 parts of the so prepared 4-h ydroxy-4'-propionyloxy-=azfi diethyl stilbene by the method described in Example 2. The product obtained is the monotetracetyl-fl-glucoside of 4-hydroxy-4'-propionyloxy-:p-diethylstilbene.

When using other mono-esters of 4:4-dihydroxy-a:p-diethyl-stilbenes produced in the same manner as the mono-acetate, such as the monobenzoate or mono-acetate, there may be obtained by analogous reaction the corresponding glucosides, such as the mono-tetracetyl-,8-glucoside of tained besides the octa-acetyl-bis-glucoside of melting point 227-230 C. described in Example 1.

This application is a continuation in part of our application Serial No. 257.736 filed February 21, 1939, now Patent No. 2,270,380.

What we claim is:

1. The compoimds of the formula wherein R is a lower aliphatic-acylated monosaccharide radical, and R is a member of the'group consisting of hydrogen, a lower aliphatic acid radical, a lower aromatic acid radical, and a free and lower aliphatic-acylated monosaccharide radical.

2. The compounds or the formula wherein R is a lower aliphatic-acylated glucose radical.

3. The compounds of the formulawherein R is an acetylated glucose radical and R V is a lower aliphatic acyl radical.

4. The mOno-tetracetyl-fi-glycoside of 4:4'-

dihydroxy-az e-diethyl-stilbene.

5. The mono-tetracetyl-fl-glucoside of 4-oxy- 4 -acetoxya ,B-diethylstilbene.

i '6. A process for the manufacture of monosaocharide derivatives, which comprises reacting 4- hydroxy-4'-acyloxy-a:p-diethyl-stilbene with an etherifying derivative selected from the group consisting of the lower aliphatic acyl and acyloxyhalogen compounds of the saccharides, mixed with a catalyst useful in furthering etherification.

7. A process for the manufacture of monosaccharide derivatives, which comprises reacting!- hydroxy-'-acyloxy-a:p-diethyi-stiibene with a penta-acetylglucose mixed with para-toluenesulionic acid. A

8. A process for the manufacture of monosac- 5 charide derivatives, which comprises reacting 4- charide derivatives, which comprises reacting 4- hydroxy -4'- acyloxy -:pdiethyl stilbene with penta-acetylgiucose mixed with para-toluenesulfonic acid, and then treating the product thus 15 obtained with sodium ethylate.

10. A process as defined in claim 6, and comprising the further step of treating the resultant product with a hydrolyzing agent.

KARL MIESCHER. WERNER. FISCHER. JULES BEER. 

